Steven E. Lindley

Serotonin Transporter Polymorphism, Memory, and Hippocampal Volume in the Elderly: Association and Interaction with Cortisol

The s allele variant of the serotonin transporter gene (5-HTT) has recently been observed to moderate the relationship of stress to depression and anxiety. To date no study has considered interactive effects of 5-HTT genotype, stress and hypothalamic–pituitary–adrenal (HPA) function on cognition in healthy, older adults, which may reflect developmental, functional or neurodegenerative effects of the serotonin transporter polymorphism. We investigated whether 5-HTT genotype interacts with cumulative life stress and HPA-axis measures of waking and diurnal cortisol slope to impact cognition in 154 non-depressed, older adults. Structural images of hippocampal volume were acquired on a subsample of 56 participants. The 5-HTT s allele was associated with both significantly lower delayed recall and higher waking cortisol levels. Presence of the s allele interacted with higher waking cortisol to negatively impact memory. We also observed a significant interaction of higher waking cortisol and the s allele on lower hippocampal volume. Smaller hippocampi and higher cortisol were associated with lower delayed recall only in s allele carriers. No impact or interactions of cumulative life stress with 5-HTT or cortisol were observed. This is the first investigation to identify an association of the 5-HTT s allele with poorer memory function in older adults. The interactive effects of the s allele and waking cortisol levels on reduced hippocampal volume and lower memory suggest that the negative effect of the serotonin polymorphism on memory is mediated by the HPA axis. Further, given the significant association of the s allele with higher waking cortisol in our investigation, future studies may be needed to evaluate the impact of the serotonin transporter polymorphism on any neuropsychiatric or behavioral outcome which is influenced by HPA axis function in older adults.

Evidence That Hypothalamic Periventricular Dopamine Neurons Innervate the Intermediate Lobe of the Rat Pituitary

The purpose of the present study was to provide neurochemical and endocrinological evidence that dopamine (DA) neurons terminating in the intermediate lobe of the rat pituitary originate in the periventricular nucleus of the hypothalamus. One week following surgical separation of the periventricular nucleus from the mediobasal hypothalamus, DA and 3,4-dihydroxyphenyl-acetic acid (DOPAC) concentrations in the intermediate lobe were reduced by 50%, and this was accompanied by an increase in plasma alpha-melanocyte-stimulating hormone (alpha-MSH) concentrations. In contrast, this procedure had no effect on concentrations of prolactin in the plasma, or DA or DOPAC in the median eminence, the region of the mediobasal hypothalamus containing terminals of tuberoinfundibular DA neurons. Electrical stimulation of the periventricular nucleus increased the ratio of DOPAC/DA in the intermediate lobe and reduced the concentrations of alpha-MSH in the plasma, whereas in these same animals the DOPAC/DA ratio in the median eminence and concentrations of prolactin in the plasma were unaltered. These results indicate that approximately 50% of all the DA neurons terminating in the intermediate lobe of the rat pituitary originate in or project through the periventricular nucleus of the hypothalamus, and that these DA neurons regulate the secretion of alpha-MSH from intermediate lobe melanotrophs.

Basal and Dexamethasone Suppressed Salivary Cortisol Concentrations in a Community Sample of Patients with Posttraumatic Stress Disorder

BACKGROUND Posttraumatic stress disorder (PTSD) has been associated with lower concentrations of cortisol and enhanced suppression of cortisol by dexamethasone, although discrepancies exist among reports. The objective of the study was to determine the pattern of cortisol responses in patients seeking treatment for PTSD resulting from a variety of traumatic experiences and to test whether cortisol responses are significantly related to childhood trauma, severity of symptoms, or length of time since trauma. METHODS Salivary cortisol was measured at 8 AM, 4 PM, and 10 PM on 2 consecutive days before and after a 10 PM dose of .5 mg dexamethasone in 17 psychotropic medication and substance-free subjects with PTSD and 17 matched control subjects. RESULTS Repeated-measures analysis of variance (ANOVA) of the baseline salivary cortisol concentrations demonstrated a significant effect for group with higher concentrations in the PTSD group but no significant differences in responses to dexamethasone. The presence of childhood abuse did not significantly affect salivary cortisol concentrations, and there was no correlation between predexamethasone cortisol and either the severity of PTSD symptoms or the time since the index trauma. CONCLUSIONS Neither low basal concentrations nor enhanced suppression of cortisol are consistent markers of a PTSD diagnosis.

Separation induced changes in squirrel monkey hypothalamic-pituitary-adrenal physiology resemble aspects of hypercortisolism in humans

When separated from groups, squirrel monkeys respond with significant increases in plasma cortisol and adrenocorticotropic hormone (ACTH). While cortisol remains elevated above pre-separation levels, significant reductions occur in ACTH. Monkeys that respond with greater increases in cortisol subsequently exhibit greater reductions in ACTH, which suggests that reductions in ACTH are mediated by corticosteroid feedback. Monkeys that respond with greater increases in cortisol also tend to exhibit greater cerebrospinal fluid levels of the dopamine metabolite HVA, but not the norepinephrine metabolite MHPG, or corticotropin-releasing factor (CRF). Attenuation of corticosteroid feedback with metyrapone results in significant increases in circulating ACTH, and in older monkeys increases plasma HVA. Similar findings in humans have been reported in clinical studies of hypercortisolism and major depression.

3,4-Dihydroxyphenylacetic acid concentrations in the intermediate lobe and neural lobe of the posterior pituitary gland as an index of tuberohypophysial dopaminergic neuronal activity

Tuberohypophysial dopamine (DA) neurons terminate in the intermediate and neural lobes of the posterior pituitary. The objective of this study was to determine if concentrations of 3,4-dihydroxyphenylacetic acid (DOPAC), a major metabolite of DA in these regions, reflect the activity of tuberohypophysial DA neurons. The concentrations of DOPAC and DA in the intermediate lobe were approximately twice those in the neural lobe, so that the ratios of DOPAC/DA were similar between lobes. The administration of a monoamine oxidase inhibitor pargyline produced a rapid decline (by 5 min) of DOPAC concentrations in both the intermediate and neural lobes. The administration of nomifensine, an inhibitor of DA uptake at the nerve terminal, produced a modest 33% decline in DOPAC concentrations in the intermediate lobe, but was without effect in the neural lobe. Activation of tuberohypophysial DA neurons by electrical stimulation of the pituitary stalk increased both the rate of DA synthesis (accumulation of dihydroxyphenylalanine (DOPA) after administration of the decarboxylase inhibitor NSD 1015) and the concentrations of DOPAC in the intermediate and neural lobes. Administration of the DA antagonist haloperidol increased, and the DA agonist apomorphine decreased both the rate of DOPA accumulation and DOPAC concentrations in the intermediate lobe but not the neural lobe. The results of the present study demonstrate that: (1) elimination of DOPAC from the intermediate lobe and neural lobe is rapid and alterations in DOPAC concentrations reflect dynamic changes in metabolism of DA; (2) DA which is released and recaptured is a minor contributor to DOPAC concentrations; and (3) alterations in the activity of tuberohypophysial DA neurons are accompanied by corresponding changes in DOPAC concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

A randomized, double-blind, placebo-controlled trial of augmentation topiramate for chronic combat-related posttraumatic stress disorder.

Background: Topiramate, a novel anticonvulsant, has been reported to rapidly reduce symptoms of posttraumatic stress disorder (PTSD) in an open-label trial. The present study was designed as a test of topiramates efficacy as adjunctive therapy in a 7-week, randomized, double-blind, placebo-controlled trial. Methods: Forty male veterans with PTSD in a residential treatment program were randomized to flexible-dose topiramate or placebo augmentation. The primary outcome measures were PTSD symptom severity and global symptom improvement. Results: Baseline Clinician-Administered PTSD Scale scores were 62.1 ± 13.9 for placebo and 61.0 ± 22.2 for topiramate. There was a high dropout rate from the study (55% topiramate; 25% placebo), with 40% of topiramate and 10% of placebo dropping because of adverse events (AEs). No significant treatment effects of topiramate versus placebo were observed for the primary treatment outcomes. Subjects reporting central nervous system-related AEs and with higher baseline severity of depression were more likely to discontinue because of AEs. Conclusions: Primary outcome measures failed to demonstrate a significant effect for topiramate over placebo; however, high dropout rate in the treatment group prohibits definitive conclusions about the efficacy of topiramate in this population.

Glucocorticoid antagonists in neuropsychotic disorders

Neuropsychiatric disorders often involve considerable psychological stress and elevated cortisol activity. Glucocorticoid receptors have relatively low affinity for cortisol and are found distributed throughout the brain, particularly in the frontal cortex and hippocampus. In recent years, glucocorticoid receptors antagonists have been actively studied in both animal models of several disorders as well as a potential treatment in specific types of neuropsychiatric patients. Data from these various studies are reviewed with an emphasis on seven clinical disorders or problems: major depression with psychotic features, bipolar disorder, schizophrenia, cognitive disorders, (e.g., Alzheimers disease and mild cognitive impairment), cognitive side effects of electroconvulsive therapy, and weight gain with atypical antipsychotic agents. Potential benefits and limitations are discussed.

Glucocorticoid Effects on Mesotelencephalic Dopamine Neurotransmission

Multiple neurochemical estimates were used to examine peripheral corticosterone (CORT) effects in dopaminergic terminal regions. Acute CORT administration, which elevated plasma CORT (5 h), slightly decreased dihydroxyphenylacetic acid (DOPAC) to dopamine (DA) ratios in the striatum but not in other regions examined. Two weeks of adrenalectomy (ADX) increased both medial prefrontal cortex DOPAC/DA and homovanillic acid (HVA)/DA and striatal HVA/DA. A reciprocal pattern of changes was observed with CORT replacement in ADX animals. In contrast, CORT replacement in ADX animals did not significantly influence tyrosine hydroxylase content, basal dihydroxyphenylalanine (DOPA) accumulation after NSD 1015 treatment or the decline in DA after alpha-methyl-para-tyrosine, suggesting that neither DA neuronal activity nor release are altered by CORT. Moreover, neither gamma-hydroxybutyric acid lactone-induced increases in DOPA accumulation or stress-induced increases in DA utilization were influenced by CORT replacement, indicating that neither autoreceptor regulation of DA synthesis nor acute stress regulation of DA utilization are changed by CORT. The findings are most consistent with direct inhibition of basal DA metabolism in the medial prefrontal cortex and striatum. The possible physiological and behavioral significance of this inhibition is being further explored.

Cholesterol and serotonin: Seeking a possible link between blood cholesterol and CSF 5-HIAA

The parallel findings relating impulsive/violent behavior to decreases in plasma cholesterol and CNS serotonin led us to perform two retrospective analyses of a possible 5-HIAA-cholesterol relationship in partially overlapping samples of men who were psychiatric inpatients and community volunteers

Psychotic Symptoms in Posttraumatic Stress Disorder

Recent data suggest that the presence of psychotic symptoms in patients suffering from posttraumatic stress disorder (PTSD) may represent an underrecognized and unique subtype of PTSD. Among combat veterans with PTSD, 30% to 40% report auditory or visual hallucinations and/or delusions. The presence of psychotic symptoms in PTSD is associated with a more severe level of psychopathology, similar to that of chronic schizophrenia. In this review, the differential diagnosis of psychotic symptoms in PTSD is discussed, including possible comorbid schizophrenia, psychotic depression, substance-induced psychosis, and personality disorder. A recent biologic study supporting the existence of a unique subtype of PTSD with psychotic features is also addressed, as are the similarities between PTSD with psychotic features and psychotic depression disorder. Finally, data on the treatment implications of psychotic symptoms in PTSD are presented. The intriguing recent findings on psychotic symptoms in PTSD need further investigation in noncombat-related PTSD populations before findings can be generalized to all individuals with PTSD.